Highly Branched Sulfated Glycopolymers as Mucin Mimetics.

Mucins are highly complex glycoproteins that form protective and lubricating barriers around epithelial surfaces, e.g., in the respiratory tract, to protect against pathogens.

Application of Lactation Physiologically Based Pharmacokinetic Modeling to Predict Milk Exposure of Passively Diffused Drugs.

Physiologically based pharmacokinetic (PBPK) models have gained interest as a tool for predicting drug transfer to human milk and assessing the exposure levels in infants. Our group previously developed an integrated lactation PBPK model framework to understand the transfer of drugs into milk and the resulting exposure in infants. As a part of the framework, the current paper focuses on performance of lactation PBPK models to predict maternal plasma and milk concentrations for drugs that are not substrates of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters-atenolol, escitalopram, and alprazolam.

Challenging Traditional ADME Assumptions for Physiologically Based Pharmacokinetic Models for Intravenous Administration of Iron-Carbohydrate Nanomedicines: Potential Utility of Gold Nanoparticle Models as a Roadmap.

Intravenous iron-carbohydrate complexes are a class of nanomedicines that are widely used globally to treat iron deficiency and iron deficiency anemia associated with a wide spectrum of disease states. Despite being widely used in clinical practice for more than seven decades, the understanding of their in vivo disposition including tissue biodistribution and kinetics of the nanoparticle degradation at the cellular level is not well-understood. Moreover, the critical quality attributes that influence in vivo pharmacokinetics have not been fully defined.

Digital lifestyle management application (levidex) for empowerment and health behaviour change in early multiple sclerosis - Results of the randomised controlled POWER@MS1 trial.

Background: This randomised controlled trial investigated the effect of a personalised digital lifestyle management application ('levidex') on inflammatory disease activity in newly diagnosed people with MS (pwMS), compared to a non-personalised application ('dexilev') that covered similar lifestyle-related content.

Methods: Participants ( = 234) were recruited from July 2019 to April 2022 in 20 study centres in Germany and randomised to levidex (intervention group (IG), = 115) or 'dexilev' (control group (CG), = 119). Follow-up data was collected over 1-2 years.

Establishing a Quantitative Framework for Combined Oral Contraceptives: Evaluating the Impact of Drug-Drug Interactions on Exposure and Clinical (Surrogate) Efficacy Endpoints.

According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI-mediated changes in exposure directly translate into clinical efficacy across progestins.

Translation of a Human-Based Malaria-on-a-Chip Phenotypic Disease Model for In Vivo Applications.

In 2023 malaria claimed ≈600000 lives, with 90% of those deaths attributed to the Plasmodium falciparum parasite. This resurgence in mortality emphasizes the necessity of adopting alternative models to accelerate therapeutic development. The Malaria-on-a-Chip model used here incorporated human liver, spleen, and endothelium with P.

Association of initiating CYP2D6-metabolized opioids with risks of adverse outcomes in older adults receiving antidepressants: A retrospective cohort study.

Background: The safety of pharmacokinetic opioid-antidepressant interactions may be affected by the sequence in which the drug is initiated. Previous literature showed that initiation of cytochrome P450 (CYP) 2D6-inhibiting versus CYP2D6-neutral antidepressants concomitantly with existing CYP2D6-metabolized opioids (i.e.

Crowdsourcing Proposal Supporting Patient Engagement in Parkinson's Disease: A Digital Research Environment (DRE)-Enabled, Patient Swarm Approach to Develop QSP Models.

Seeking to incorporate the patient voice into a collaborative effort to develop a quantitative system pharmacology (QSP) model for Parkinson's disease (PD) we propose the creation of a "patient swarm" in conjunction with a digital research environment (DRE) connecting various academic centers of excellence and their compute environments to promote data sharing and model collaboration with patient engagement. Patients, their advocates, and other stakeholders are welcome to join the crowdsourcing effort with the intention of reading the relevant source literature and contributing thoughts on model priors and model development while sharing their personal disease trajectories. Training materials are provided from experienced modelers and clinical stakeholders and maintained on the DRE as a resource for the "Swarm.

High-Throughput Screening for Prescribing Cascades Among Real-World Angiotensin-II Receptor Blockers (ARBs) Initiators.

Objective: Angiotensin-II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescription(s), known as prescribing cascades. We aimed to identify potential ARB-induced prescribing cascades using high-throughput sequence symmetry analysis.

Methods: Using claims data from a national sample of Medicare beneficiaries (2011-2020), we identified new ARB users aged ≥66 years with continuous enrollment ≥360 days before and ≥180 days after ARB initiation.

High-Throughput Screening for Prescribing Cascades Among Real-World Angiotensin-Converting Enzyme Inhibitor Initiators.

Purpose: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly prescribed, but their adverse effects may prompt new drug prescription(s), known as prescribing cascades (PCs). We aimed to identify potential ACEI-induced PCs using high-throughput sequence symmetry analysis.

Methods: Using claims data from a national sample of Medicare beneficiaries (2011-2020), we identified new ACEI users aged ≥ 66 years with continuous enrollment ≥ 360 days before and ≥ 180 days after ACEI initiation.

Unrelieved pain and risk of opioid use disorder or overdose in older adults prescribed opioids.

It is unclear to what extent unrelieved pain, the most common motive for prescription opioid misuse, is associated with risks of opioid use disorder (OUD) and opioid overdose (OD) among older adults with prescribed opioids. This retrospective cohort study was conducted among Health and Retirement Study (HRS) participants with linked Medicare claims data between 2006 and 2021. Participants aged 65 years or older with chronic pain who had received at least 1 opioid prescription entered the cohort in an HRS-assessed pain assessment (index) between 2008 and 2020.

Establishment of a Biomarker-Directed Clinical Endpoint Model for Early-Stage Parkinson's Disease Patients.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by dopaminergic cell death in the substantia nigra. While the interplay between dopamine loss and symptoms is well-recognized, a respective quantitative link has yet to be established. The objective was to establish a biomarker-directed clinical endpoint model for early-stage PD patients.

Outcomes of Discontinuing Long-Term Opioid Therapy among Older Cancer Survivors in Long-Term Care Settings.

Objectives: Clinical decisions to continue or discontinue long-term opioid therapy (LTOT; ≥3 months) for older cancer survivors remain challenging due to limited evidence on the risks and benefits of this treatment practice. This study aims to examine the associations of discontinuing LTOT with clinical and opioid-related adverse event (ORAE) outcomes among older cancer survivors residing in long-term care (LTC) settings.

Designs: This retrospective cohort study analyzed data from the 100% Medicare nursing home sample from 2010 to 2021.

Prescription opioid use and cognitive function in older adults with chronic pain: A population-based longitudinal cohort study.

Introduction: Whether prescription opioid exposure, duration, and dose are associated with cognitive function remains inconclusive.

Methods: A longitudinal cohort among 3097 older adults with chronic pain and without dementia was conducted using Health and Retirement Study (HRS) linked to Medicare data from 2006 to 2020. Prescription opioid exposure, cumulative use for ≥ 90 days, and high-dose use (≥ 90 morphine milligram equivalents [MME] daily) were assessed biennially.

Microphysiological system to address the opioid crisis: A novel multi-organ model of acute opioid overdose and recovery.

Opioids have been the primary method used to manage pain for hundreds of years, however the increasing prescription rate of these drugs in the modern world has led to a public health crisis of overdose related deaths. Naloxone is the current standard treatment for opioid overdose rescue, but it has not been fully investigated for potential off-target toxicity effects. The current methods for pharmaceutical development do not correlate well with pre-clinical animal studies compared to clinical results, creating a need for improved methods for therapeutic evaluation.

Sulfated Glycosaminoglycans as Inhibitors for Chlamydia Infections: Molecular Weight and Sulfation Dependence.

Glycosaminoglycans (GAGs) play a pivotal role in pathogen attachment and entry into host cells, where the interaction with GAGs is critical for a diverse range of bacteria and viruses. This study focuses on elucidating the specific interactions between sulfated GAGs and the adhesin OmcB (Outer membrane complex protein B) of Chlamydia species, examining how structural characteristics of GAGs, such as sulfation degree and molecular weight, influence their binding affinity and thereby affect bacterial infectivity. A surface-based binding assay is established to determine the binding constants of OmcB with various GAGs.

Unravelling sources of variability on rocuronium pharmacokinetics: Implications for prolonged recovery in older patients.

Aims: Residual neuromuscular blockade (RNB) commonly occurs when using neuromuscular blockers and increases the risk for pulmonary complications, such as airway obstruction and severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability in recovery time, contributing to an increased risk for RNB. This study aimed to identify and characterize the sources of variability in rocuronium exposure and response via a population pharmacokinetic/pharmacodynamic (PK/PD) analysis and to apply the developed PK/PD model to investigate clinical implications.

Worse survival of hepatocellular cancer patients with membranous insulin receptor overexpression.

Hepatocellular cancer (HCC) therapy is in need for an ideal companion diagnostic. Preclinical experimental studies have identified the insulin receptor (IR) and its synergistic counterpart, the IGF1 receptor (IGF1R), as relevant in HCC development, and the ligands IGF1 and IGF2 have been found to be elevated in HCC. This study aimed to bridge the gap to the clinical setting and explore whether the IR or the IGF1R would be of prognostic significance and would be associated with clinicopathologic parameters in HCC patients.

Disease Progression Mathematical Modeling With a Case Study on Hepatitis B Virus Infection.

Chronic Hepatitis B presents a significant health and socioeconomic burden. The risk of hepatocellular carcinoma remains elevated although treatments are available. Achieving an optimal treatment regimen necessitates a deep comprehension of the dynamic relationship between the virus and its host across disease states.

Selective Glycan Presentation in Liquid-Ordered or -Disordered Membrane Phases and its Effect on Lectin Binding.

Glycan-protein interactions play a key role in various biological processes from fertilization to infections. Many of these interactions take place at the glycocalyx-a heavily glycosylated layer at the cell surface. Despite its significance, studying the glycocalyx remains challenging due to its complex, dynamic, and heterogeneous nature.